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1
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Chen C, Wang L. Aging and metabolic dysfunction-associated steatotic liver disease: a bidirectional relationship. Front Med 2025:10.1007/s11684-025-1133-7. [PMID: 40316793 DOI: 10.1007/s11684-025-1133-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 01/09/2025] [Indexed: 05/04/2025]
Abstract
In recent years, aging and cellular senescence have triggered an increased interest in corresponding research fields. Evidence shows that the complex aging process is involved in the development of many chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In fact, aging has a tremendous effect on the liver, leading to a gradual decline in the metabolism, detoxification and immune functions of the liver, which in turn increases the risk of liver disease. These changes can be based on the aging of liver cells (hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells, and Kupffer cells). Similarly, patients with liver diseases exhibit increases in the aging phenotype and aging cells, often manifesting as faster physical functional decline, which is closely related to the promoting effect of liver disease on aging. This review summarizes the interplay between MASLD/MASH development and aging, aiming to reveal the complex relationships that exacerbate one another. Moreover, the corresponding schemes for delaying aging or treating diseases are discussed to provide a basis for the development of effective prevention and treatment strategies in the future.
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Affiliation(s)
- Chen Chen
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
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2
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Wen F, Yang G, Yu S, Liu H, Liao N, Liu Z. Mesenchymal stem cell therapy for liver transplantation: clinical progress and immunomodulatory properties. Stem Cell Res Ther 2024; 15:320. [PMID: 39334441 PMCID: PMC11438256 DOI: 10.1186/s13287-024-03943-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 09/16/2024] [Indexed: 09/30/2024] Open
Abstract
Although liver transplantation (LT) is an effective strategy for end-stage liver diseases, the shortage of donor organs and the immune rejection hinder its widespread implementation in clinical practice. Mesenchymal stem cells (MSCs) transplantation offers a promising approach for patients undergoing liver transplantation due to their immune regulatory capabilities, hepatic protection properties, and multidirectional differentiation potential. In this review, we summarize the potential applications of MSCs transplantation in various LT scenarios. MSCs transplantation has demonstrated effectiveness in alleviating hepatic ischemia-reperfusion injury, enhancing the viability of liver grafts, preventing acute graft-versus-host disease, and promoting liver regeneration in split LT therapy. We also discuss the clinical progress, and explore the immunomodulatory functions of MSCs in response to both adaptive and innate immune responses. Furthermore, we emphasize the interactions between MSCs and different immune cells, including T cells, B cells, plasma cells, natural killer cells, dendritic cells, Kupffer cells, and neutrophils, to provide new insights into the immunomodulatory properties of MSCs in adoptive cell therapy.
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Affiliation(s)
- Fuli Wen
- Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fuzhou, 350001, China
| | - Guokai Yang
- Department of Nephrology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, P. R. China
| | - Saihua Yu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350028, P. R. China
| | - Haiyan Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350028, P. R. China
| | - Naishun Liao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350028, P. R. China.
| | - Zhengfang Liu
- Department of Traditional Chinese Medicine, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350028, P. R. China.
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3
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Sanfeliu-Redondo D, Gibert-Ramos A, Gracia-Sancho J. Cell senescence in liver diseases: pathological mechanism and theranostic opportunity. Nat Rev Gastroenterol Hepatol 2024; 21:477-492. [PMID: 38485755 DOI: 10.1038/s41575-024-00913-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/12/2024] [Indexed: 06/30/2024]
Abstract
The liver is not oblivious to the passage of time, as ageing is a major risk factor for the development of acute and chronic liver diseases. Ageing produces alterations in all hepatic cells, affecting their phenotype and function and worsening the prognosis of liver disease. The ageing process also implies the accumulation of a cellular state characterized by a persistent proliferation arrest and a specific secretory phenotype named cellular senescence. Indeed, senescent cells have key roles in many physiological processes; however, their accumulation owing to ageing or pathological conditions contributes to the damage occurring in chronic diseases. The aim of this Review is to provide an updated description of the pathophysiological events in which hepatic senescent cells are involved and their role in liver disease progression. Finally, we discuss novel geroscience therapies that could be applied to prevent or improve liver diseases and age-mediated hepatic deregulations.
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Affiliation(s)
- David Sanfeliu-Redondo
- Liver Vascular Biology Laboratory, IDIBAPS Biomedical Research Institute - Hospital Clínic de Barcelona & CIBEREHD, Barcelona, Spain
| | - Albert Gibert-Ramos
- Liver Vascular Biology Laboratory, IDIBAPS Biomedical Research Institute - Hospital Clínic de Barcelona & CIBEREHD, Barcelona, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Laboratory, IDIBAPS Biomedical Research Institute - Hospital Clínic de Barcelona & CIBEREHD, Barcelona, Spain.
- Department of Visceral Surgery and Medicine, Inselspital - University of Bern, Bern, Switzerland.
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4
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Wang Y, Qiu H, Chen S, Li D, Zhao X, Guo M, Li N, Chen C, Qin M, Zhou Y, Xiao D, Zhao J, Xu L. MicroRNA-7 deficiency ameliorates d-galactose-induced aging in mice by regulating senescence of Kupffer cells. Aging Cell 2024; 23:e14145. [PMID: 38494663 PMCID: PMC11166366 DOI: 10.1111/acel.14145] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 02/05/2024] [Accepted: 03/01/2024] [Indexed: 03/19/2024] Open
Abstract
Aging is intricately linked to immune system dysfunction. Recent studies have highlighted the biological function of microRNA-7 (miR-7) as a novel regulator of immune cell function and related diseases. However, the potential role of miR-7 in aging remains unexplored. Here, we investigated the contribution of miR-7 to d-gal-induced aging in mice, focusing on its regulation of senescent Kupffer cells. Our findings revealed that miR-7 deficiency significantly ameliorated the aging process, characterized by enhanced CD4+ T-cell activation. However, the adoptive transfer of miR-7-deficient CD4+T cells failed to improve the age-related phenotype. Further analysis showed that miR-7 deficiency significantly reduced IL-1β production in liver tissue, and inhibiting IL-1β in vivo slowed down the aging process in mice. Notably, IL-1β is mainly produced by senescent Kupffer cells in the liver tissue of aging mice, and miR-7 expression was significantly up-regulated in these cells. Mechanistically, KLF4, a target of miR-7, was down-regulated in senescent Kupffer cells in aging mouse model. Furthermore, miR-7 deficiency also modulated the NF-κB activation and IL-1β production in senescent Kupffer cells through KLF4. In conclusion, our findings unveil the role of miR-7 in d-gal-induced aging in mice, highlighting its regulation of KLF4/NF-κB/IL-1β pathways in senescent Kupffer cells. This research may enhance our understanding of miRNA-based aging immune cells and offer new avenues for new intervention strategies in aging process.
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Affiliation(s)
- Ya Wang
- Department of ImmunologyZunyi Medical UniversityZunyiGuizhouChina
- Key Laboratory of Gene Detection and Treatment of Guizhou ProvinceZunyiGuizhouChina
| | - Hui Qiu
- Department of ImmunologyZunyi Medical UniversityZunyiGuizhouChina
- Key Laboratory of Gene Detection and Treatment of Guizhou ProvinceZunyiGuizhouChina
| | - Shipeng Chen
- Department of ImmunologyZunyi Medical UniversityZunyiGuizhouChina
- Key Laboratory of Gene Detection and Treatment of Guizhou ProvinceZunyiGuizhouChina
| | - Dongmei Li
- Department of ImmunologyZunyi Medical UniversityZunyiGuizhouChina
- Key Laboratory of Gene Detection and Treatment of Guizhou ProvinceZunyiGuizhouChina
| | - Xu Zhao
- Key Laboratory of Gene Detection and Treatment of Guizhou ProvinceZunyiGuizhouChina
- School of MedicineGuizhou UniversityGuiyangGuizhouChina
| | - Mengmeng Guo
- Department of ImmunologyZunyi Medical UniversityZunyiGuizhouChina
- Key Laboratory of Gene Detection and Treatment of Guizhou ProvinceZunyiGuizhouChina
| | - Nana Li
- Key Laboratory of Gene Detection and Treatment of Guizhou ProvinceZunyiGuizhouChina
| | - Chao Chen
- Department of ImmunologyZunyi Medical UniversityZunyiGuizhouChina
- Key Laboratory of Gene Detection and Treatment of Guizhou ProvinceZunyiGuizhouChina
| | - Ming Qin
- Department of ImmunologyZunyi Medical UniversityZunyiGuizhouChina
- Key Laboratory of Gene Detection and Treatment of Guizhou ProvinceZunyiGuizhouChina
| | - Ya Zhou
- Department of Medical PhysicsZunyi Medical UniversityZunyiGuizhouChina
| | | | - Juanjuan Zhao
- Department of ImmunologyZunyi Medical UniversityZunyiGuizhouChina
- Key Laboratory of Gene Detection and Treatment of Guizhou ProvinceZunyiGuizhouChina
| | - Lin Xu
- Department of ImmunologyZunyi Medical UniversityZunyiGuizhouChina
- Key Laboratory of Gene Detection and Treatment of Guizhou ProvinceZunyiGuizhouChina
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Dwivedi SD, Bhoi A, Pradhan M, Sahu KK, Singh D, Singh MR. Role and uptake of metal-based nanoconstructs as targeted therapeutic carriers for rheumatoid arthritis. 3 Biotech 2024; 14:142. [PMID: 38693915 PMCID: PMC11058151 DOI: 10.1007/s13205-024-03990-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 04/15/2024] [Indexed: 05/03/2024] Open
Abstract
Rheumatoid Arthritis (RA) is a chronic autoimmune systemic inflammatory disease that affects the joints and other vital organs and diminishes the quality of life. The current developments and innovative treatment options have significantly slowed disease progression and improved their quality of life. Medicaments can be delivered to the inflamed synovium via nanoparticle systems, minimizing systemic and undesirable side effects. Numerous nanoparticles such as polymeric, liposomal, and metallic nanoparticles reported are impending as a good carrier with therapeutic properties. Other issues to be considered along are nontoxicity, nanosize, charge, optical property, and ease of high surface functionalization that make them suitable carriers for drug delivery. Metallic nanoparticles (MNPs) (such as silver, gold, zinc, iron, titanium oxide, and selenium) not only act as good carrier with desired optical property, and high surface modification ability but also have their own therapeutical potential such as anti-oxidant, anti-inflammatory, and anti-arthritic properties, making them one of the most promising options for RA treatment. Regardless, cellular uptake of MNPs is one of the most significant criterions for targeting the medication. This paper discusses the numerous interactions of nanoparticles with cells, as well as cellular uptake of NPs. This review provides the mechanistic overview on MNPs involved in RA therapies and regulation anti-arthritis response such as ability to reduce oxidative stress, suppressing the release of proinflammatory cytokines and expression of LPS induced COX-2, and modulation of MAPK and PI3K pathways in Kuppfer cells and hepatic stellate cells. Despite of that MNPs have also ability to regulates enzymes like glutathione peroxidases (GPxs), thioredoxin reductases (TrxRs) and act as an anti-inflammatory agent.
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Affiliation(s)
- Shradha Devi Dwivedi
- University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur, Chhattisgarh 492010 India
| | - Anita Bhoi
- School of Studies in Biotechnology, Pt. Ravishankar Shukla University, Raipur, C.G 492010 India
| | - Madhulika Pradhan
- Gracious College of Pharmacy, Abhanpur Raipur, Chhattisgarh 493661 India
| | - Keshav Kant Sahu
- School of Studies in Biotechnology, Pt. Ravishankar Shukla University, Raipur, C.G 492010 India
| | - Deependra Singh
- University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur, Chhattisgarh 492010 India
| | - Manju Rawat Singh
- University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur, Chhattisgarh 492010 India
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6
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Li M, Zhang J, Fang J, Xin Y, Zhu H, Ding X. Pre-administration of human umbilical cord mesenchymal stem cells has better therapeutic efficacy in rats with D-galactosamine-induced acute liver failure. Int Immunopharmacol 2024; 130:111672. [PMID: 38377851 DOI: 10.1016/j.intimp.2024.111672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 02/05/2024] [Accepted: 02/07/2024] [Indexed: 02/22/2024]
Abstract
BACKGROUND Acute liver failure (ALF) is characterized by an intense systemic inflammatory response, single or multiple organ system failure and high mortality. However, specific and effective treatments for ALF patients are still lacking. According to the current investigation, human umbilical cord mesenchymal stem cells (hUCMSCs) have shown remarkable potential to enhance the functional recovery of injured livers. We aimed to investigate the therapeutic effects of time-differentiated hUCMSCs administration regimens on ALF. METHODS The rat model of ALF was induced by D-galactosamine (D-gal), and hUCMSCs were administered via the tail vein 12 h before or 2 h after induction. The potential mechanisms of hUCMSCs in treatment of ALF, regulation cell subset and secretion of inflammatory factors, were verified by co-culturing with PBMCs in vitro. Liver function indicators were detected by an automatic biochemistry analyzer and inflammatory factors were obtained by ELISA detection. The distribution of hUCMSCs in rats after administration was followed by quantitative real-time fluorescence PCR. RESULTS The findings of the study discovered that administration of hUCMSCs 12 h prior to surgery could significantly improve the survival rate of rats, stabilize various liver function indicators in serum levels of ALT, AST, T-BIL, or ALB diminish inflammatory infiltration in liver tissue, and inhibit the secretion of inflammatory factors. CONCLUSION Our data showed that pre-transplantation of hUCMSCs had a better therapeutic effect on ALF rats, providing empirical evidence for preclinical studies. Thus, the timing of hUCMSCs transplantation is necessary for the optimal clinical treatment effect.
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Affiliation(s)
- Min Li
- Sinoneural Cell Engineering Group Holdings., Co, Ltd, No.1188, Lianhang Road, Shanghai 201100, PR China
| | - Jigang Zhang
- Clinical Research Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.100 Haining Road, Shanghai 200080, PR China; Shanghai Engineering Research Center of Translational Medicine of Cell Therapy, Shanghai 200080, PR China
| | - Jingmeng Fang
- Sinoneural Cell Engineering Group Holdings., Co, Ltd, No.1188, Lianhang Road, Shanghai 201100, PR China
| | - Yuan Xin
- Sinoneural Cell Engineering Group Holdings., Co, Ltd, No.1188, Lianhang Road, Shanghai 201100, PR China
| | - Hao Zhu
- Sinoneural Cell Engineering Group Holdings., Co, Ltd, No.1188, Lianhang Road, Shanghai 201100, PR China.
| | - Xueying Ding
- Clinical Research Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.100 Haining Road, Shanghai 200080, PR China; Shanghai Engineering Research Center of Translational Medicine of Cell Therapy, Shanghai 200080, PR China.
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7
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Singh S, Sharma K, Sharma H. Green Extracts with Metal-based Nanoparticles for Treating Inflammatory Diseases: A Review. Curr Drug Deliv 2024; 21:544-570. [PMID: 37278036 DOI: 10.2174/1567201820666230602164325] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 04/24/2023] [Accepted: 05/04/2023] [Indexed: 06/07/2023]
Abstract
Globally, high death rates and poor quality of life are caused mainly by inflammatory diseases. Corticosteroids, which may have systemic side effects and would enhance the risk of infection, are the common forms of therapy. The field of nanomedicine has created composite nanoparticles that carry a pharmacological carrier and target ligands for distribution to sites of inflammation with less systemic toxicity. However, their relatively large size often causes systemic clearance. An interesting approach is metal-based nanoparticles that naturally reduce inflammation. They are made not only to be small enough to pass through biological barriers but also to allow label-free monitoring of their interactions with cells. The following literature review discusses the mechanistic analysis of the anti-inflammatory properties of several metal-based nanoparticles, including gold, silver, titanium dioxide, selenium, and zinc oxide. Current research focuses on the mechanisms by which nanoparticles infiltrate cells and the anti-inflammatory techniques using herbal extracts-based nanoparticles. Additionally, it provides a brief overview of the literature on many environmentally friendly sources employed in nanoparticle production and the mechanisms of action of various nanoparticles.
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Affiliation(s)
- Sonia Singh
- Institute of Pharmaceutical Research GLA University, 17km Stone, NH-2, Mathura-Delhi Road Mathura, Chaumuhan, Uttar Pradesh-281406, India
| | - Khushi Sharma
- Institute of Pharmaceutical Research GLA University, 17km Stone, NH-2, Mathura-Delhi Road Mathura, Chaumuhan, Uttar Pradesh-281406, India
| | - Himanshu Sharma
- Department of Computer Engineering & Applications GLA University, 17km Stone, NH-2, Mathura-Delhi Road Mathura, Chaumuhan, Uttar Pradesh-281406, India
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8
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Kiouptsi K, Casari M, Mandel J, Gao Z, Deppermann C. Intravital Imaging of Thrombosis Models in Mice. Hamostaseologie 2023; 43:348-359. [PMID: 37857297 DOI: 10.1055/a-2118-2932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2023] Open
Abstract
Intravital microscopy is a powerful tool to study thrombosis in real time. The kinetics of thrombus formation and progression in vivo is studied after inflicting damage to the endothelium through mechanical, chemical, or laser injury. Mouse models of atherosclerosis are also used to induce thrombus formation. Vessels of different sizes and from different vascular beds such as carotid artery or vena cava, mesenteric or cremaster arterioles, can be targeted. Using fluorescent dyes, antibodies, or reporter mouse strains allows to visualize key cells and factors mediating the thrombotic processes. Here, we review the latest literature on using intravital microscopy to study thrombosis as well as thromboinflammation following transient middle cerebral artery occlusion, infection-induced immunothrombosis, and liver ischemia reperfusion.
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Affiliation(s)
- Klytaimnistra Kiouptsi
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
| | - Martina Casari
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Jonathan Mandel
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Zhenling Gao
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Carsten Deppermann
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
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9
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Yang H, Chen J, Li J. Isolation, culture, and delivery considerations for the use of mesenchymal stem cells in potential therapies for acute liver failure. Front Immunol 2023; 14:1243220. [PMID: 37744328 PMCID: PMC10513107 DOI: 10.3389/fimmu.2023.1243220] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 08/18/2023] [Indexed: 09/26/2023] Open
Abstract
Acute liver failure (ALF) is a high-mortality syndrome for which liver transplantation is considered the only effective treatment option. A shortage of donor organs, high costs and surgical complications associated with immune rejection constrain the therapeutic effects of liver transplantation. Recently, mesenchymal stem cell (MSC) therapy was recognized as an alternative strategy for liver transplantation. Bone marrow mesenchymal stem cells (BMSCs) have been used in clinical trials of several liver diseases due to their ease of acquisition, strong proliferation ability, multipotent differentiation, homing to the lesion site, low immunogenicity and anti-inflammatory and antifibrotic effects. In this review, we comprehensively summarized the harvest and culture expansion strategies for BMSCs, the development of animal models of ALF of different aetiologies, the critical mechanisms of BMSC therapy for ALF and the challenge of clinical application.
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Affiliation(s)
| | | | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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10
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Liver ischaemia-reperfusion injury: a new understanding of the role of innate immunity. Nat Rev Gastroenterol Hepatol 2022; 19:239-256. [PMID: 34837066 DOI: 10.1038/s41575-021-00549-8] [Citation(s) in RCA: 194] [Impact Index Per Article: 64.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/29/2021] [Indexed: 02/08/2023]
Abstract
Liver ischaemia-reperfusion injury (LIRI), a local sterile inflammatory response driven by innate immunity, is one of the primary causes of early organ dysfunction and failure after liver transplantation. Cellular damage resulting from LIRI is an important risk factor not only for graft dysfunction but also for acute and even chronic rejection and exacerbates the shortage of donor organs for life-saving liver transplantation. Hepatocytes, liver sinusoidal endothelial cells and Kupffer cells, along with extrahepatic monocyte-derived macrophages, neutrophils and platelets, are all involved in LIRI. However, the mechanisms underlying the responses of these cells in the acute phase of LIRI and how these responses are orchestrated to control and resolve inflammation and achieve homeostatic tissue repair are not well understood. Technological advances allow the tracking of cells to better appreciate the role of hepatic macrophages and platelets (such as their origin and immunomodulatory and tissue-remodelling functions) and hepatic neutrophils (such as their selective recruitment, anti-inflammatory and tissue-repairing functions, and formation of extracellular traps and reverse migration) in LIRI. In this Review, we summarize the role of macrophages, platelets and neutrophils in LIRI, highlight unanswered questions, and discuss prospects for innovative therapeutic regimens against LIRI in transplant recipients.
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11
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Li M, Yang L. Autophagy in the liver. AUTOPHAGY IN HEALTH AND DISEASE 2022:161-179. [DOI: 10.1016/b978-0-12-822003-0.00014-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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12
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Zhou JH, Lu X, Yan CL, Sheng XY, Cao HC. Mesenchymal stromal cell-dependent immunoregulation in chemically-induced acute liver failure. World J Stem Cells 2021; 13:208-220. [PMID: 33815670 PMCID: PMC8006015 DOI: 10.4252/wjsc.v13.i3.208] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 01/08/2021] [Accepted: 02/15/2021] [Indexed: 02/06/2023] Open
Abstract
Drug-induced liver injury (DILI), which refers to liver damage caused by a drug or its metabolites, has emerged as an important cause of acute liver failure (ALF) in recent years. Chemically-induced ALF in animal models mimics the pathology of DILI in humans; thus, these models are used to study the mechanism of potentially effective treatment strategies. Mesenchymal stromal cells (MSCs) possess immunomodulatory properties, and they alleviate acute liver injury and decrease the mortality of animals with chemically-induced ALF. Here, we summarize some of the existing research on the interaction between MSCs and immune cells, and discuss the possible mechanisms underlying the immuno-modulatory activity of MSCs in chemically-induced ALF. We conclude that MSCs can impact the phenotype and function of macrophages, as well as the differentiation and maturation of dendritic cells, and inhibit the proliferation and activation of T lymphocytes or B lymphocytes. MSCs also have immuno-modulatory effects on the production of cytokines, such as prostaglandin E2 and tumor necrosis factor-alpha-stimulated gene 6, in animal models. Thus, MSCs have significant benefits in the treatment of chemically-induced ALF by interacting with immune cells and they may be applied to DILI in humans in the near future.
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Affiliation(s)
- Jia-Hang Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Xuan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Cui-Lin Yan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Xin-Yu Sheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Hong-Cui Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China.
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13
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Gomzikova MO, Aimaletdinov AM, Bondar OV, Starostina IG, Gorshkova NV, Neustroeva OA, Kletukhina SK, Kurbangaleeva SV, Vorobev VV, Garanina EE, Persson JL, Jeyapalan J, Mongan NP, Khaiboullina SF, Rizvanov AA. Immunosuppressive properties of cytochalasin B-induced membrane vesicles of mesenchymal stem cells: comparing with extracellular vesicles derived from mesenchymal stem cells. Sci Rep 2020; 10:10740. [PMID: 32612100 PMCID: PMC7330035 DOI: 10.1038/s41598-020-67563-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 06/05/2020] [Indexed: 12/13/2022] Open
Abstract
Extracellular vesicles derived from mesenchymal stem cells (MSCs) represent a novel approach for regenerative and immunosuppressive therapy. Recently, cytochalasin B-induced microvesicles (CIMVs) were shown to be effective drug delivery mediators. However, little is known about their immunological properties. We propose that the immunophenotype and molecular composition of these vesicles could contribute to the therapeutic efficacy of CIMVs. To address this issue, CIMVs were generated from murine MSC (CIMVs-MSCs) and their cytokine content and surface marker expression determined. For the first time, we show that CIMVs-MSCs retain parental MSCs phenotype (Sca-1+, CD49e+, CD44+, CD45−). Also, CIMVs-MSCs contained a cytokine repertoire reflective of the parental MSCs, including IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12(p40), IL-13, IL-17, CCL2, CCL3, CCL4, CCL5, CCL11, G-CSF, GM-CSF and TNF-α. Next, we evaluated the immune-modulating properties of CIMVs-MSCs in vivo using standard preclinical tests. MSCs and CIMVs-MSCs reduced serum levels of anti-sheep red blood cell antibody and have limited effects on neutrophil and peritoneal macrophage activity. We compared the immunomodulatory effect of MSCs, CIMVs and EVs. We observed no immunosuppression in mice pretreated with natural EVs, whereas MSCs and CIMVs-MSCs suppressed antibody production in vivo. Additionally, we have investigated the biodistribution of CIMVs-MSCs in vivo and demonstrated that CIMVs-MSCs localized in liver, lung, brain, heart, spleen and kidneys 48 h after intravenous injection and can be detected 14 days after subcutaneous and intramuscular injection. Collectively our data demonstrates immunomodulatory efficacy of CIMVs and supports their further preclinical testing as an effective therapeutic delivery modality.
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Affiliation(s)
- M O Gomzikova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008. .,M.M. Shemyakin-Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia, 117997.
| | - A M Aimaletdinov
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008
| | - O V Bondar
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008
| | - I G Starostina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008
| | - N V Gorshkova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008
| | - O A Neustroeva
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008
| | - S K Kletukhina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008
| | - S V Kurbangaleeva
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008
| | - V V Vorobev
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008
| | - E E Garanina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008
| | - J L Persson
- Department of Translational Medicine, Lund University, 205 02, Malmö, Sweden.,Department of Molecular Biology, Umeå University, Umeå, 901 87, USA
| | - J Jeyapalan
- Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Science, University of Nottingham, Nottingham, LE12 5RD, UK
| | - N P Mongan
- Department of Translational Medicine, Lund University, 205 02, Malmö, Sweden.,Department of Pharmacology, Weill Cornell Medicine, 1300 York Ave., New York, NY, 10065, USA
| | - S F Khaiboullina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008.,Department of Microbiology and Immunology, Reno School of Medicine, University of Nevada, Reno, NV, USA
| | - A A Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008. .,M.M. Shemyakin-Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia, 117997.
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14
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Cheng W, Meng W, Gu Y. Metalloprotease Adam10 inhibition mitigates acute liver injury via repression of intrahepatic inflammation. Minerva Med 2020; 113:506-512. [PMID: 32512977 DOI: 10.23736/s0026-4806.20.06655-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Acute liver injury (ALI) is associated with the occurrence and progress of intrahepatic inflammation. Recent studies have shown that Adam10, a significant member of metalloproteinase family, has modulated the inflammation level in various neurologic diseases. However, it is elusive whether Adam10 regulation exert a hepatic protective effect on ALI by the suppression of inflammation level. The study aimed to explore the regulated function of Adam10 on acute liver injury. METHODS C57BL/6J mice (eight-week-old, male) were carried out intraperitoneal injection of tetrachloromethane (CTC) to provoke ALI. Adam 10 loaded in Adeno-associated viral vectors (AAV-Adam 10) or short hairpin RNA loaded in lentivirus aimed at murine Adam 10 mRNA (sh-RNA-Adam 10) were respectively delivered to mice via tail intravenous injection to achieve overexpression or silence of Adam 10. Western blotting, reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), immumohistochemical (IHC) and hematoxylin and eosin (HE) staining were conducted to measure Adam 10 alteration, inflammation level, histology and liver function. RESULTS We show that the expression of Adam 10 markedly increases in CTC-induced injured liver tissues. Moreover, we demonstrate that the knockdown of Adam 10 attenuates the intrahepatic inflammation and protects hepatic histology and function in ALI mice, however the overexpression of Adam10 aggravates inflammation and liver lesion. CONCLUSIONS The above suggested that the inhibition of Adam 10 ameliorates ALI through inhibiting inflammation. Our research provides novel view on the Adam 10 modulation of process of ALI by the inflammation aspect and verify a potential target for the therapy of ALI in the future.
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Affiliation(s)
- Weihua Cheng
- Departments of Hepatobiliary, Pancreatic and Splenic Surgery, Baoji Central Hospital, Baoji, China
| | - Wei Meng
- Department of Infectious Disease, Binzhou People's Hospital, Binzhou, China
| | - Yihai Gu
- Department of Traditional Chinese Medicine, Sixth People's Hospital of Qingdao, Qingdao, China -
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15
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Weigle S, Martin E, Voegtle A, Wahl B, Schuler M. Primary cell-based phenotypic assays to pharmacologically and genetically study fibrotic diseases in vitro. J Biol Methods 2019; 6:e115. [PMID: 31453262 PMCID: PMC6706098 DOI: 10.14440/jbm.2019.285] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 03/20/2019] [Accepted: 03/20/2019] [Indexed: 12/27/2022] Open
Abstract
Ongoing tissue repair and formation and deposition of collagen-rich extracellular matrix in tissues and organs finally lead to fibrotic lesions and destruction of normal tissue/organ architecture and function. In the lung, scarring is observed in asthma, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis to various degrees. At the cellular level immune cells, fibroblasts and epithelial cells are all involved in fibrotic processes. Mechanistically, fibroblast to myofibroblast transformation and epithelial to mesenchymal transition are major drivers of fibrosis. Amongst others, both processes are controlled by transforming growth factor beta-1 (TGFβ-1), a growth factor upregulated in idiopathic pulmonary fibrosis lungs. Phenotypic assays with primary human cells and complex disease-relevant readouts become increasingly important in modern drug discovery processes. We describe high-content screening based phenotypic assays with primary normal human lung fibroblasts and primary human airway epithelial cells. For both cell types, TGFβ-1 stimulation is used to induce fibrotic phenotypes in vitro, with alpha smooth muscle actin and collagen-I as readouts for FMT and E-cadherin as a readout for EMT. For each assay, a detailed image analysis protocols is described. Treatment of both cell types with TGFβ-1 and a transforming growth factor beta receptor inhibitor verifies the suitability of the assays for pharmacological interventions. In addition, the assays are compatible for siRNA and Cas9-ribonucleoprotein transfections, and thus are useful for genetic target identification/validation by modulating gene expression.
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Affiliation(s)
| | | | | | | | - Michael Schuler
- Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Drug Discovery Sciences, 88397 Biberach an der Riss, Germany
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16
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Agarwal H, Nakara A, Shanmugam VK. Anti-inflammatory mechanism of various metal and metal oxide nanoparticles synthesized using plant extracts: A review. Biomed Pharmacother 2019; 109:2561-2572. [DOI: 10.1016/j.biopha.2018.11.116] [Citation(s) in RCA: 167] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 11/14/2018] [Accepted: 11/25/2018] [Indexed: 12/14/2022] Open
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17
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de Aro AA, Carneiro GD, Teodoro LFR, da Veiga FC, Ferrucci DL, Simões GF, Simões PW, Alvares LE, de Oliveira ALR, Vicente CP, Gomes CP, Pesquero JB, Esquisatto MAM, de Campos Vidal B, Pimentel ER. Injured Achilles Tendons Treated with Adipose-Derived Stem Cells Transplantation and GDF-5. Cells 2018; 7:cells7090127. [PMID: 30200326 PMCID: PMC6162699 DOI: 10.3390/cells7090127] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 08/17/2018] [Accepted: 08/23/2018] [Indexed: 12/22/2022] Open
Abstract
Tendon injuries represent a clinical challenge in regenerative medicine because their natural repair process is complex and inefficient. The high incidence of tendon injuries is frequently associated with sports practice, aging, tendinopathies, hypertension, diabetes mellitus, and the use of corticosteroids. The growing interest of scientists in using adipose-derived mesenchymal stem cells (ADMSC) in repair processes seems to be mostly due to their paracrine and immunomodulatory effects in stimulating specific cellular events. ADMSC activity can be influenced by GDF-5, which has been successfully used to drive tenogenic differentiation of ADMSC in vitro. Thus, we hypothesized that the application of ADMSC in isolation or in association with GDF-5 could improve Achilles tendon repair through the regulation of important remodeling genes expression. Lewis rats had tendons distributed in four groups: Transected (T), transected and treated with ADMSC (ASC) or GDF-5 (GDF5), or with both (ASC+GDF5). In the characterization of cells before application, ADMSC expressed the positive surface markers, CD90 (90%) and CD105 (95%), and the negative marker, CD45 (7%). ADMSC were also differentiated in chondrocytes, osteoblast, and adipocytes. On the 14th day after the tendon injury, GFP-ADMSC were observed in the transected region of tendons in the ASC and ASC+GDF5 groups, and exhibited and/or stimulated a similar genes expression profile when compared to the in vitro assay. ADMSC up-regulated Lox, Dcn, and Tgfb1 genes expression in comparison to T and ASC+GDF5 groups, which contributed to a lower proteoglycans arrangement, and to a higher collagen fiber organization and tendon biomechanics in the ASC group. The application of ADMSC in association with GDF-5 down-regulated Dcn, Gdf5, Lox, Tgfb1, Mmp2, and Timp2 genes expression, which contributed to a lower hydroxyproline concentration, lower collagen fiber organization, and to an improvement of the rats’ gait 24 h after the injury. In conclusion, although the literature describes the benefic effect of GDF-5 for the tendon healing process, our results show that its application, isolated or associated with ADMSC, cannot improve the repair process of partial transected tendons, indicating the higher effectiveness of the application of ADMSC in injured Achilles tendons. Our results show that the application of ADMSC in injured Achilles tendons was more effective in relation to its association with GDF-5.
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Affiliation(s)
- Andrea Aparecida de Aro
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
- Biomedical Sciences Graduate Program, Herminio Ometto University Center⁻UNIARARAS, 13607-339 Araras, SP, Brazil.
| | - Giane Daniela Carneiro
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
| | - Luis Felipe R Teodoro
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
| | - Fernanda Cristina da Veiga
- Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
| | - Danilo Lopes Ferrucci
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
| | - Gustavo Ferreira Simões
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
| | - Priscyla Waleska Simões
- Engineering, Modeling and Applied Social Sciences Center (CECS), Biomedical Engineering Graduate Program (PPGEBM), Universidade Federal do ABC (UFABC), Alameda da Universidade s/n, 09606-045 São Bernardo do Campo, SP, Brazil.
| | - Lúcia Elvira Alvares
- Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
| | - Alexandre Leite R de Oliveira
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
| | - Cristina Pontes Vicente
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
| | - Caio Perez Gomes
- Department of Biophysics, Federal University of Sao Paulo⁻Unifesp, Pedro de Toledo, 699, 04039-032 Sao Paulo, SP, Brazil.
| | - João Bosco Pesquero
- Department of Biophysics, Federal University of Sao Paulo⁻Unifesp, Pedro de Toledo, 699, 04039-032 Sao Paulo, SP, Brazil.
| | - Marcelo Augusto M Esquisatto
- Biomedical Sciences Graduate Program, Herminio Ometto University Center⁻UNIARARAS, 13607-339 Araras, SP, Brazil.
| | - Benedicto de Campos Vidal
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
| | - Edson Rosa Pimentel
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas⁻UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil.
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Delire B, Lebrun V, Selvais C, Henriet P, Bertrand A, Horsmans Y, Leclercq IA. Aging enhances liver fibrotic response in mice through hampering extracellular matrix remodeling. Aging (Albany NY) 2017; 9:98-113. [PMID: 27941216 PMCID: PMC5310658 DOI: 10.18632/aging.101124] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 11/24/2016] [Indexed: 02/06/2023]
Abstract
Clinical data identify age as a factor for severe liver fibrosis. We evaluate whether and how aging modulates the fibrotic response in a mouse model. Liver fibrosis was induced by CCl4 injections (thrice weekly for 2 weeks) in 7 weeks- and 15 months-old mice (young and old, respectively). Livers were analyzed for fibrosis, inflammation and remodeling 48 and 96 hours after the last injection. Old mice developed more severe fibrosis compared to young ones as evaluated by sirius red morphometry. Expression of pro-fibrogenic genes was equally induced in the two age-groups but enhanced fibrolysis in young mice was demonstrated by a significantly higher Mmp13 induction and collagenase activity. While fibrosis resolution occurred in young mice within 96 hours, no significant fibrosis attenuation was observed in old mice. Although recruitment of monocytes-derived macrophages was similar in young and old livers, young macrophages had globally a remodeling phenotype while old ones, a pro-fibrogenic phenotype. Moreover, we observed a higher proportion of thick fibers and enhanced expression of enzymes involved in collagen maturation in old mice. CONCLUSION Impaired fibrolysis of a matrix less prone to remodeling associated with a pro-inflammatory phenotype of infiltrated macrophages contribute to a more severe fibrosis in old mice.
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Affiliation(s)
- Bénédicte Delire
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium
| | - Valérie Lebrun
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium
| | - Charlotte Selvais
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium
| | - Patrick Henriet
- Cell Biology Unit, de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Amélie Bertrand
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium
| | - Yves Horsmans
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium.,Department of Hepato-Gastroenterology, Cliniques Universitaires Saint-Luc and Institute of Clinical Research, Université catholique de Louvain, Brussels, Belgium
| | - Isabelle A Leclercq
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium
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Hamid M, Liu D, Abdulrahim Y, Khan A, Qian G, Huang K. Inactivation of Kupffer Cells by Selenizing Astragalus Polysaccharides Prevents CCl 4-Induced Hepatocellular Necrosis in the Male Wistar Rat. Biol Trace Elem Res 2017; 179:226-236. [PMID: 28243851 DOI: 10.1007/s12011-017-0970-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 02/14/2017] [Indexed: 01/29/2023]
Abstract
Selenizing astragalus polysaccharides-3 (sAPS3) was prepared by nitric acid-sodium selenite method. The effects of sAPS3 on carbon tetrachloride (CCl4) induced hepatocellular necrosis, and its underlying mechanisms were studied in male Wistar rats. Hepatic damage was induced by intraperitoneal injection of CCl4 twice a week, for 3 weeks. Meanwhile, the rats in addition to CCl4 were also exposed to sodium selenite (SS), astragalus polysaccharides (APS), SS + APS or sAPS3, in parallel by oral gavage once a day for 3 weeks. At the end of 3 weeks, blood and liver tissue were taken. Serum was collected to test the levels of alanine aminotransferase, aspartate aminotransferase and antioxidant status parameters. Liver tissue was collected for histopathological examination and determination of messenger RNA (mRNA) expression levels of CD68, TNF-α, IL-1β and ATG7 followed by the measurements of CD68, IL-1β and LC3II by immunohistochemistry assay (IHC), or TNF-α by immunofluorescence assay (IFA). The results showed that sAPS3 effectively ameliorated CCl4 induced hepatocellular necrosis and inflammation and significantly decreased the levels of aspartate aminotransferase, alanine aminotransferase, malondialdehyde and the expression levels of Kupffer cells (KCs)-specific biomarker CD68 and proinflammatory cytokines produced by activated KCs such as IL-1β and TNF-α (P < 0.01). While increasing the levels of total antioxidant capacity, glutathione, glutathione peroxidase and superoxide dismutase (P < 0.05) and reduced the expression levels of a key regulator of autophagy in KCs ATG7 or LC3II (P < 0.05). These findings indicate that sAPS3 could ameliorate CCl4-induced hepatocellular necrosis by inactivation of Kupffer cells and its activity may be superior to the application of selenium, APS or combination of selenium with APS.
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Affiliation(s)
- Mohammed Hamid
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowl, Nanjing Agricultural University, Nanjing, 210095, China
- College of Veterinary Sciences, University of Nyala, Nyala, Sudan
| | - Dandan Liu
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowl, Nanjing Agricultural University, Nanjing, 210095, China
| | - Yassin Abdulrahim
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowl, Nanjing Agricultural University, Nanjing, 210095, China
- College of Veterinary Sciences, University of Nyala, Nyala, Sudan
| | - Alamzeb Khan
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowl, Nanjing Agricultural University, Nanjing, 210095, China
| | - Gang Qian
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowl, Nanjing Agricultural University, Nanjing, 210095, China
| | - Kehe Huang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China.
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowl, Nanjing Agricultural University, Nanjing, 210095, China.
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Zhu L, Wang G, Fischbach S, Xiao X. Suppression of microRNA-205-5p in human mesenchymal stem cells improves their therapeutic potential in treating diabetic foot disease. Oncotarget 2017; 8:52294-52303. [PMID: 28881730 PMCID: PMC5581029 DOI: 10.18632/oncotarget.17012] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 03/30/2017] [Indexed: 12/15/2022] Open
Abstract
Diabetes is a prevalent disease endangering human health, while diabetic foot disease (DF) is one of the most severe complications of diabetes. Mesenchymal stem cells (MSCs) have been used in DF treatment, taking advantage of the differentiation potential of MSCs into endothelial cells and their production and secretion of trophic factors like vascular endothelial growth factor (VEGF). Molecular modification of MSCs to improve their therapeutic effects has been recently applied in treating other diseases, but not yet in DF. Here, we found that micoRNA-205-5p (miR-205-5p) is expressed in human MSCs, and miR-205-5p inhibits protein translation of VEGF through its interaction with 3'-UTR of the VEGF mRNA. Expression of antisense of miR-205-5p (as-miR-205-5p) significantly increased both cellular and secreted VEGF by MSCs, which significantly improved the therapeutic effects of MSCs on DF-associated wound healing in diabetic NOD/SCID mice. Together, our data suggest that miR-205-5p suppression in MSCs may improve their therapeutic effects on DF, seemingly through augmentation of VEGF-mediated vascularization.
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Affiliation(s)
- Lingyan Zhu
- Department of Endocrinology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Gongxian Wang
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Shane Fischbach
- Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA15224, USA
| | - Xiangwei Xiao
- Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA15224, USA
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Pyrrolidine dithiocarbamate alleviates the anti-tuberculosis drug-induced liver injury through JAK2/STAT3 signaling pathway: An experimental study. ASIAN PAC J TROP MED 2017. [PMID: 28647191 DOI: 10.1016/j.apjtm.2017.05.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVE To study the effect of pyrrolidine dithiocarbamate (PDTC) on the anti-tuberculosis drug-induced liver injury and the molecular mechanism. METHODS Clean male SD rats were selected as experimental animals and randomly divided into normal group, model group, PDTC group and AG490 group. Animal model of anti-tuberculosis drug-induced liver injury was established by intragastric administration isoniazid + rifampicin. PDTC group received intraperitoneal injection of PDTC, and AG490 group received intraperitoneal injection of AG490. Twenty-eight days after intervention, the rats were executed, and the liver injury indexes, inflammation indexes and oxidative stress indexes in serum as well as JAK2/STAT3 expression, liver injury indexes, inflammation indexes and oxidative stress indexes in liver tissue were determined. RESULTS p-JAK2, p-STAT3, TNF-α, IL-1β, IL-6, ROS, 8-OHdG and MDA expression in liver tissue as well as TBIL, ALT, AST, γ-GT, TNF-α, IL-1β, IL-6, 8-OHdG and MDA levels in serum of model group were significantly higher than those of normal group while p-JAK2, p-STAT3, TNF-α, IL-1β, IL-6, ROS, 8-OHdG and MDA expression in liver tissue as well as TBIL, ALT, AST, γ-GT, TNF-α, IL-1β, IL-6, 8-OHdG and MDA levels in serum of PDTC group and AG490 group were significantly lower than those of model group. CONCLUSIONS PDTC can inhibit the inflammation and oxidative stress mediated by JAK2/STAT3 signaling pathway to alleviate the anti-tuberculosis drug-induced liver injury.
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